Defining genetic factors that predict response to therapy (pharmacogenetics) has the potential of providing important biomarkers of response. The overall goal of this project is to examine the role of pharmacogenetics in the efficacy of adjuvant therapy with the aromatase inhibitor, anastrozole, compared to anastrozole combined with the pure antiestrogen, fulvestrant, for metastatic breast cancer in postmenopausal patients. These agents are relatively new, and pharmacogenetic studies are lacking. We hypothesize that genetic variants in the anastrozole and fulvestrant metabolic pathways, as well as in their molecular targets (the aromatase enzyme and estrogen receptors) will influence therapeutic outcomes. The specific aims of the project are (1) to define the major enzymes responsible for the metabolism of these drugs;(2) to test the hypothesis that functional genotypes in drug metabolizing enzymes are related to the occurrence of treatment-related toxicities, time to progression and overall survival among treated breast cancer patients and (3) to test the hypothesis that intratumoral expression levels of drug metabolizing enzymes influence response to therapy. This study will be performed in the context of an ongoing Southwest Oncology Group-sponsored clinical trial (S0226) and will take advantage of outcome data and biological specimens collected for this trial. We will perform in vitro metabolism studies using human liver tissue fractions and specific recombinant enzymes to identify major metabolic enzymes. We will also genotype for polymorphisms in the identified enzymes, as well as in aromatase and estrogen receptors and in enzymes involved in the production of hot flashes. Finally, using a tissue microarray produced in S0226, we will determine the role of enzyme expression in efficacy of therapy. Backed by the support of the SWOG Breast Correlative Studies Committee, this project will begin to define the role of host genetic variation in response to treatment with anastrozole and fulvestrant in postmenopausal metastatic breast cancer.